Recent studies indicate that genetic material derived from tumor sites can be identified in the blood of cancer patients. Studies have demonstrated the potential of this genetic material to be used as a source of screening patients for the treatment of actionable somatic mutations (so called ?liquid biopsy?). This approach permits screening of virtually all patients, even those whose tumor sites would introduce significant risk for needle biopsy. In addition, it has been reported that the use of serial assessment of circulating tumor DNA (ctDNA) is feasible for the determination of treatment response and disease progression. Another possible approach for assessment of tumor derived somatic mutations relies on purification of exosomes shed by tumors into circulation. These exosomes mainly contain RNA in addition to some DNA. A new method claims to permit the simultaneous purification of exosomal nucleic acids plus ctDNA from plasma. If proven reliable, this method should provide higher levels of analytes that subsequently leads to increased sensitivity of detection of somatic mutations. Another possible advantage of exosomes is the ability to use targeted RNAseq for detection of gene fusions. Most ctNA studies have focused on detection of a single known somatic mutation or have used targeted sequencing panels. The amount of ctNA found within plasma is small compared to normal germline sequence, therefore, high depth next generation sequencing (NGS) or digital PCR have proven to be the best methods for detection. The advantage of NGS is that a single well developed clinical grade assay will suffice to detect most clinically relevant and treatment actionable somatic variants. However, detection of somatic variants found in the background of 1,000?s fold excess of normal germline sequence requires determination of assay noise and would benefit from reduction of noise. Although the field is rapidly evolving, minimal knowledge exists as to the best approach to achieve reliable and sensitive detection of circulating tumor nucleic acids (ctNA). The Division of Cancer Treatment and Diagnosis (DCTD) would like to determine the best practices for collecting and analyzing circulating nucleic acid (including exosomal nucleic acid) in clinical studies and implement a clinical grade NGS assay with higher throughput.